Highly purified pharmaceutical grade tasimelteon

ABSTRACT

A process for preparing a batch of highly purified, pharmaceutical grade tasimelteon comprises analyzing a batch of tasimelteon synthesized under GMP conditions for the presence of one or more identified impurities.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S. patentapplication Ser. No. 16/123,303, filed 6 Sep. 2018, which is acontinuation application of then-co-pending U.S. patent application Ser.No. 15/117,734, filed 10 Aug. 2016, now U.S. Pat. No. 10,071,977, whichis the US National Phase of PCT Application Ser. No. PCT/US2015/015564,filed 12 Feb. 2015, which claimed the benefit of then-co-pending USProvisional Application Ser. No. 61/938,932, filed 12 Feb. 2014, andthen-co-pending US Provisional Application Ser. No. 62/087,394, filed 04Dec. 2014, each of which is incorporated herein as though fully setforth.

FIELD OF THE INVENTION

The disclosure relates generally to the synthesis of tasimelteon. Insome embodiments, impurities, which may be by-products or degradationproducts, are analyzed and controlled in order to keep the impuritiesbelow pre-set specifications.

BACKGROUND OF THE INVENTION

Tasimelteon, N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-propionamide, is a melatonin agonist useful in the treatment ofpersons suffering from certain sleep-related disorders.

A synthesis of tasimelteon is disclosed, e.g., in Example 2 of U.S. PatNo. 5,856,529. The end step synthesis in that example comprises reactionof ((1R,2R)-2-(2, 3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine withpropionyl chloride. Synthesis of the methanamine intermediate isdescribed in Preparation 24 and comprises reaction of((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)) cyclopropanecarboxaldehyde withhydroxylamine hydrochloride. Synthesis of the carboxaldehydeintermediate is described in Preparation 18 and comprises palladiumcatalyzed cyclization of a propenoyl intermediate, specifically,(1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) propenoyl)-2,10-camphorsultam.

SUMMARY OF THE INVENTION

In one illustrative embodiment, the invention relates to a process forsynthesizing highly purified, pharmaceutical grade tasimelteon, theprocess comprising:

-   -   (a) propionylating ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methanamine or a salt thereof to yield tasimelteon;    -   (b) crystallizing the tasimelteon produced in step (a);    -   (c) assaying the crystallized tasimelteon from step (b) for the        presence of one or both of Impurity 5        (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamido)methyl)        cyclopropyl)methyl)propionamide) and Impurity 6        (2-hydroxy-6-(2-(propionamidomethyl) cyclopropyl)phenethyl        2-(2-hydroxyethyl)-3-(2-(propionamidomethyl) cyclopropyl)phenyl        carbonate); and    -   (d)(i) if the crystallized tasimelteon meets pre-set        specifications for Impurity 5 or Impurity 6, or both, then        collecting the highly purified, pharmaceutical grade tasimelteon        or    -   (d)(ii) if the crystallized tasimelteon fails to meet pre-set        specifications for Impurity 5 or Impurity 6, or both, then        further purifying the tasimelteon and repeating steps (c) and        (d), or discarding the batch.

In another illustrative embodiment, the invention relates to a processfor preparing a batch of highly purified, pharmaceutical gradetasimelteon, the process comprising:

(a) analyzing a batch of tasimelteon synthesized under conditions ofGood Manufacturing Practices (“GMP conditions”) for the presence of anidentified impurity(ies) that is(are) one or more of:

-   -   N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide        (Impurity 1),    -   N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide        (Impurity 2),    -   1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methyl)urea (Impurity 3),    -   N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide        (Impurity 4)    -   N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)(propionamido)methyl)        cyclopropyl)methyl)propionamide (Impurity 5),    -   2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl        2-(2-hydroxyethyl) -3-(2-(propionamidomethyl)cyclopropyl)phenyl        carbonate (Impurity 6),    -   N-(((1R,2R)-2-(3-Oxo-2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methyl)propionamide (Impurity 7) and        (b) if the batch meets pre-set specifications for the amount of        the one or more of Impurity 1, Impurity 2, Impurity 3, Impurity        4, Impurity 5, Impurity 6, or Impurity 7, then continuing to        process the tasimelteon to prepare bulk tasimelteon drug        substance for formulation or        (c) if the tasimelteon does not meet said pre-set        specifications, then further purifying (such as by        recrystallization, trituration, extraction, or chromatography)        the tasimelteon and repeating steps (a) and (b) or discarding        the batch.

In another illustrative embodiments, further specifications forcontinuing to process the tasimelteon are pre-set, e.g., that thetasimelteon is not less than (“NLT”) 95.0%, or NLT 98.0% pure (by areaunder the curve) and/or that the amount of any other single impurity isNMT 0.10 area %.

In another illustrative embodiment, the invention relates to a processfor preparing a batch of tasimelteon drug product (i.e., tasimelteonplus excipients) wherein release of a batch of tasimelteon bulk drugsubstance for use in the manufacture of the tasimelteon drug product iscontingent upon the testing and application of acceptance criteria forthe amounts of one or more of the following impurities:

-   -   N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide        (Impurity 1),    -   N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide        (Impurity 2),    -   1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methyl)urea (Impurity 3),    -   N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide        (Impurity 4)    -   N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)(propionamido)methyl)        cyclopropyl)methyl)propionamide (Impurity 5),    -   2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl        2-(2-hydroxyethyl) -3-(2-(propionamidomethyl)cyclopropyl)phenyl        carbonate (Impurity 6),    -   N-(((1R,2R)-2-(3-Oxo-2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methyl)propionamide (Impurity 7).

In a further illustrative embodiment, the invention relates to purifiedtasimelteon wherein the tasimelteon does not contain any of Impurities 1through 7 at a concentration greater than about 0.15%. In relatedillustrative embodiments, such composition does not contain anyrelated-substance impurity (i.e., an impurity that is structurallyrelated to tasimelteon such as degradation products, dimers, etc.) at aconcentration of greater than about 0.15% by weight.

DETAILED DESCRIPTION OF THE INVENTION

The synthesis of tasimelteon can result in a plurality of impuritiesfollowing the end step synthesis. An illustrative synthesis oftasimelteon is a linear process, passing through a methanamineintermediate such as by the process described in U.S. Pat. No. 5,856,529and involving four purification steps: one purification step for each ofthree isolated intermediates, as described below, as well as one for theunmilled tasimelteon drug substance. (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxylate (herein referred to as Intermediate 3 orStage 9), (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxamide (herein referred to as Intermediate 4 or Stage 10), and themethanamine intermediate (herein referred to as Intermediate 5 or Stage11) and the tasimelteon (unmilled) drug substance are each isolated bycrystallization and, if necessary, are subjected to recrystallization toimprove purity.

The inventors have discovered that in the synthesis of tasimelteon thereare certain impurities that can be formed as both by-products anddegradation products, and that these impurities can be controlled orreduced to non-detectable or acceptably detectable levels. Although notdesiring to be bound by theory, the inventors have identified some ofthese impurities on the basis of mass spectrometric, nuclear magneticresonance spectroscopic and other data. The inventors have found thatthe impurities can include one or more of:

N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide(Impurity 1),N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide(Impurity 2),1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea(Impurity 3),

N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (Impurity4),

N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamido)methyl) cyclopropyl)methyl)propionamide(Impurity 5),2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl2-(2-hydroxyethyl) -3-(2-(propionamidomethyl)cyclopropyl)phenylcarbonate (Impurity 6), andN-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (Impurity 7).

Impurities 1-3 and 5-6 may be by-products of certain steps of thesynthesis of tasimelteon, and impurities 4 and 7 may be degradationproducts.

The inventors have also found that in the synthesis of tasimelteon,there are certain additional impurities that can occur as degradationproducts, reaction byproducts, residual reagents, and residualintermediates. These additional impurities can be controlled or reducedto non-detectable or acceptably detectable levels. These impurities caninclude (+)-dehydroabietylamine, propionyl chloride, propionic acid,ethyl propionate [possibly additional potential degradants of propionylchloride], ethyl diazoacetate, Intermediates 2, 4, and 5,4-vinyl-2,3-dihydrobenzofuran (VBF),4-(2-chloroethyl)-2,3-dihydrobenzofuran (VBF-int-2), benzene, and heavymetals such as As, Al, Fe, Li, Ni, Ru, Pd, Mn, Rh, Cu, and Co.

Some such impurities, such as ethyl diazaoacetate and propionylchloride, are potentially genotoxic and must be controlled to ppm levelsin order for the bulk GMP tasimelteon to be suitable for formulationinto bulk pharmaceutical composition and subsequently distributed intopharmaceutical dosage units.

The identification of such impurities facilitates quality control andconsistency of product. With the knowledge of the identities of theseimpurities, a manufacturer of tasimelteon can set specifications for themaximum allowable amount of the impurities in bulk GMP tasimelteon,which can then be formulated into bulk pharmaceutical composition andthen distributed into pharmaceutical dosage units.

Thus, in one aspect, this invention comprises a batch of pharmaceuticalgrade, highly purified tasimelteon that has been analyzed for thepresence of any or each of these impurities and determined to have lessthan a pre-determined amount of one or more of them. The pre-determinedamounts, i.e., the pre-set specifications, for these intermediates canbe set to satisfy regulatory requirements. For example, the pre-setspecification for Impurities 1-7 and the additional impurities can be0.15 wt %. In a further embodiment, the pre-set specification can be0.10 area %, e.g., for unidentified impurities. Additionally, a pre-setspecification may include not more than (NMT) 100 ppm or NMT 10 ppm ofethyl diazaoacetate (EDA)

The impurities are detectable by analytical chemical techniques such aschromatographic and mass spectrometry techniques among others. Forexample, HPLC, GC, or other chromatography methods can be used, in whichcase the amount of one or of each of the impurities can be determined onthe basis of wt % or of area under the curve.

As used herein, abbreviations for methods and techniques may include:High-performance Liquid Chromatography (HPLC), Ultra Performance LiquidChromatography (UPLC), Supercritical fluid chromatography (SFC), Gaschromatography (GC), Good Manufacturing Practices (GMP), Current GoodManufacturing Practices (cGMP), not more than (NMT), and not less than(NLT).

References herein to percent (%) purity are based on area. Such relativequantities approximate weight % but persons skilled in the art know howto determine more precise weight % amounts if desired.

A synthesis of tasimelteon is disclosed, e.g., in Example 2 of U.S. Pat.No. 5,856,529. The end step synthesis in that example comprises reactionof ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropyl)methanamine withpropionyl chloride. Synthesis of the methanamine intermediate isdescribed in Preparation 24 and comprises reaction of((1R,2R)-2-(2,3-dihydrobenzofuran -4-yl))cyclopropanecarboxaldehyde withhydroxylamine hydrochloride. Synthesis of the carboxaldehydeintermediate is described in Preparation 18 and comprises palladiumcatalyzed cyclization of a propenoyl intermediate, specifically,((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) propenoyl)-2,10-camphorsultam.

An alternative route to the methanamine intermediate or a salt thereof(herein referred to as Intermediate 5) proceeds through(1R,2R)-2-(2,3-dihydrobenzofuran -4-yl) cyclopropanecarboxylate(Intermediate 3) to (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxamide (Intermediate 4) and then to Intermediate 5 ora salt thereof.

A synthesis of Intermediate 2 by stereoselective cyclization of4-vinyl-2,3-dihydrobenzofuran is described, e.g., in U.S. Pat. No.7,754,902.

An illustrative end-step synthesis of tasimelteon from Intermediate 5 isprovided in Scheme 6, below. In general, the synthesis comprises:

-   -   (a) propionylating ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)        cyclopropyl)methanamine or a salt thereof to yield tasimelteon;    -   (b) crystallizing the tasimelteon produced in step (a);    -   (c) assaying the crystallized tasimelteon from step (b) for the        presence of one or both of Impurity 5        (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamido)methyl)        cyclopropyl)methyl)propionamide) and Impurity 6        (2-hydroxy-6-(2-(propionamidomethyl) cyclopropyl)phenethyl        2-(2-hydroxyethyl)-3-(2-(propionamidomethyl) cyclopropyl)phenyl        carbonate); and    -   (d)(i) if the crystallized tasimelteon meets pre-set        specifications for Impurity 5 or Impurity 6, or both, then        collecting the highly purified, pharmaceutical grade tasimelteon        or    -   (d)(ii) if the crystallized tasimelteon fails to meet pre-set        specifications for Impurity 5 or Impurity 6, or both, then        further purifying the tasimelteon and repeating steps (c) and        (d), or discarding the batch.

In such end-step synthesis, the propionylating step may comprisecontacting((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a saltthereof with a propionyl halide, a propionyl anhydride, a propionylester, a propionyl amide, a propionyl imidazolide, or with propionicacid and a dehydrating agent or the product thereof. Water is abyproduct of the coupling of((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine withpropionic acid to form tasimelteon. The dehydrating agent, which is alsoknown as a peptide coupling reagent, is an agent that activatespropionic acid toward reaction with ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropyl)methanamine and consumes the byproduct, water.Commonly used dehydrating agents include but are not limited todicyclohexylcarbodiimide (DCC), DCC and an aminopyridine,N,N′-carbonyldiimidazole, chlorosilanes, Amberlyst-15, MeSO2Cl-Et3N,BF3, TiCl4, other Lewis acids, reagents of the type ArB(OH)₂,Sn[N(TMS)₂], POCl3, molecular sieves, Lawesson's reagent, and(MeO)₂POCl.

The propionylation may be carried out in the presence of an organicsolvent (e.g., ter-butyl methyl ether) and an aqueous base (e.g., NaOH),After the propionylation step and before the crystallizing step, themixture of tasimelteon may be assayed for the presence of Intermediate 5(or the free base or other salt thereof) and, if the mixture does notmeet pre-set specifications for Intermediate 5 (e.g., not more than0.15% or not more than 0.10%), then repeating step (a) or discarding themixture. After the propionylation step and before the crystallizingstep, the mixture of tasimelteon may be washed with aqueous base and theaqueous layer discarded, after which the washed mixture may be distilled(e.g., in ethanol at up to about 58° C., and less than about 100 mmHg).The crystallization step may comprise dissolving the tasimelteon bystirring and warming a mixture of the tasimelteon and a C1-C4 alkanol(e.g., about 35 to about 40° C.) and then cooling (e.g., to about 13 toabout 17° C.) while stirring. The crystallization step optionallycomprises seeding.

An illustrative synthesis of tasimelteon, in one embodiment, can includethe following reaction schemes with a number of intermediates beingsynthesized first.

Synthesis of 4-(2-Chloroethyl)-2,3-Dihydrobenzofuran (VBF-Int-2)

The synthesis of VBF-int-2 can comprise contacting and reacting2,3-Bis(2-hydroxyethyl) phenol (Triol) withN,N-dimethylchloromethyleneiminium chloride (the Vilsmeier reagent) inan organic solvent, followed by reacting the resultingN,N′-[(3-hydroxy-1,2-phenylene)-bis (ethane-2,1-diyloxymethylidene)]-bis(N-methylmethanaminium) dichloride (VBF-int-1) with triethylamine in anorganic solvent. The Vilsmeier reagent may be generated in situ fromN,N-dimethylformamide (DMF) and oxalyl chloride. Said reaction isillustrated in the following scheme:

For example, a first reaction mixture can be prepared by slowly addingoxalyl chloride (approximately 2.45-2.55 equiv) to a solution of DMF(approximately 2.45-2.55 equiv) in CH₃CN (Acetonitrile (e.g., 16% byweight DMF)) at −10±5° C. while maintaining the batch temperature at−10±5° C. Stirring may be continued at this temperature forapproximately 30-40 min to complete the formation of the Vilsmeierreagent (N,Ndimethylchloromethyleneiminium chloride) in situ. Triol(Stage 3) (1.00 equiv; e.g., 30 kg) is added to the solution of theVilsmeier reagent in portions through an addition funnel whilemaintaining the batch temperature at −10±5° C. Stirring is continued atabout −20 to about −5° C. for at least 90 min, until testing via highpressure liquid chromatography (HPLC) indicates that no more than (NMT)2.0% Triol (Stage 3) remains in solution. If necessary, the mixture canbe sampled again at 150 min and tested again for Triol levels. Followingthis, a solution of Et₃N (triethylamine (approximately 3.8-4.1 equiv))in CH₃CN (e.g., 47% by weight Et₃N) may be slowly added to the reactionmixture while maintaining the batch temperature at −10±5° C. This stepis an exothermic step. The total volume of CH₃CN should be approximately5-17 L/kg of Triol (Stage 3) input, and in one embodiment may be 10 L/kgof Triol (Stage 3) input. When the addition is complete, the mixture maybe heated to 55±5° C. for 3-3.5 hr. The mixture may then be cooled to25±5° C. and stirred for up to four increments of up to approximately 1hr each until HPLC indicates VBF-int-1 (Stage 4) NMT 2.0 area %. Tapwater (e.g., 2.3 L/kg of Triol (Stage 3)) is then added to this reactionmixture, and stirring is continued for 30-40 min. The mixture isdistilled at<100 torr and less than approximately 40° C. until no moreorganic distillate is collected. TBME (e.g., 5.6 kg/kg of triol (Stage3)) and tap water (e.g., 3.2 L/kg of Triol (Stage 3)) are then added tothe batch residue. The mixture is stirred for 30-40 min and settled for30-40 min. The aqueous layer is removed. A solution of H₃PO₄ (8.5% byweight) in aqueous brine (e.g., 5 kg of H₃PO₄ solution/kg of Triol(Stage 3)) is slowly added to the remaining organic layer. This mixturecan be stirred for 30-40 min and settled for 30-40 min. The aqueouslayer is removed once more. The organic phase can be washed one or moretimes with tap water (e.g., 5 L/kg of Triol (Stage 3)), each timestirring for approximately 30-40 minutes, settling for approximately30-40 min, and removing the aqueous layer. Following the washing withtap water, the organic layer is distilled at<100 torr and less thanapproximately 40° C. until no more distillate is collected. The batchresidue is subjected to short path distillation at 0.1-4 torr. Anydistillate boiling below 105° C. is discarded. The distillate boiling at105-130° C. is subjected to HPLC analysis. Material meeting a pre-setspecification, e.g., VBF-int-2 (Stage 5) present at not less than (NLT)95.0%, is used directly in the next step.

Synthesis of 4-Vinyl-2,3-Dihydrobenzofuran (VBF) (Stage 6)

The synthesis of VBF can comprise contacting and reacting4-(2-Chloroethyl) -2,3-dihydrobenzofuran (VBF-int-2) withtetrabutylammonium hydroxide in the presence of organic solvent. Saidreaction is illustrated in the following scheme:

In one embodiment, tetrabutylammonium hydroxide (0.78 kg/kg of VBF-int-2(Stage 5)), potassium iodide (0.09 kg/kg of VBF-int-2 (Stage 5)) andVBF-int-2 (from above (Stage 5)) is added to a mixture of TBME(tert-Butyl methyl ether) (5.60 kg/kg of VBFint-2 (Stage 5)) and 45%aqueous NaOH (4.80 kg/kg of VBF-int-2 (Stage 5)). In some embodiments,the NaOH, tetrabutylammonium hydroxide and KI charges are in the ranges7-10, 0.15-0.50 and 0.08-0.10 molar equivalents, respectively. Themixture may be heated to 50±5° C. and stirred for approximately 3-3.5hr. The mixture is then cooled to 25±5° C. and stirred for up to fourincrements of NLT 1 hr each until testing via HPLC indicates VBF-int-2Stage 5) NMT 1.0%. The mixture is settled for 20-30 min and 40-60 L ofthe aqueous layer is discharged. 16% aqueous HCl (e.g., up to 6.2 kg/kgof VBFint-2 (Stage 5)) is added slowly to the remaining mixture untilthe pH of the mixture is 9.5-10.5. If necessary, 4.5% aqueous NaOH isadded to adjust the pH into this range. The mixture can then be filteredusing TBME (1 kg/kg of VBF-int-2 (Stage 5)) to complete the transfer andthe filtrate settled for 20-30 minutes. The aqueous layer may then beremoved. 8% Na₂S₂O₃ in 9% aqueous brine (e.g., 4.3 kg of Na₂S₂O₃solution/kg of VBF-int-2 (Stage 5)) is added to the organic layer, thenthe mixture is stirred for 10-15 min and settled for 20-30 min and theaqueous layer is removed. To the organic layer is added 4% NaOH in 9%aqueous brine (e.g., 4.2 kg of NaOH solution/kg of VBF-int-2 (Stage 5))followed by stirring, settling and removal of the aqueous layer. Thenquinol (e.g., 7 g kg of VBF-int-2 (Stage 5), or 1 mol %) is added to theorganic layer and the mixture is stirred for 20-30 min. The resultingsolution is subjected to HPLC analysis for purity and assay. Materialmeeting pre-set purity specification, e.g., VBF (Stage 6) NLT 95.0 area%, is used directly in the next step. The assay result from HPLC isreported as % wt/wt.

Synthesis of (1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl) (Intermediate 3)(Stage 9)

The synthesis of Intermediate 3 (Stage 9) can comprise asymmetriccyclopropanation of 4-vinyl-2,3-dihydrobenzofuran (VBF (Stage 6)) bycontacting and reacting it with EDA in the presence of a chiralcatalyst. It can also comprise hydrolysis of the ester group of2-(2,3-dihydrobenzofuran-4-yl) -cyclopropanecarboxylic acid ethyl ester(VEC-int-1 (Stage 7)) followed by polishing resolution of2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanecarboxylic acid (Intermediate2 (Stage 8)) with (+)-dehydroabietylamine (DAA) in an organic solvent.Said reaction sequence is illustrated in the following scheme:

In one embodiment, in order to form Intermediate 3, a number ofprocesses may be utilized in preparation.

A lithium diisopropylamide (LDA) solution may be prepared. For instance,a solution of n-butyllithium (0.03 equiv; 1 M in hexanes) is added,slowly, to a solution of diisopropylamine (DISPA; 0.04 equiv; e.g., 10M) in THF at 5±5° C. After the addition is complete, stirring iscontinued at 5±5° C. for 30-40 min. The resulting solution of lithiumdiisopropylamide (LDA) is used directly for the subsequent deprotonationof BTBSC ((R,R)-(-)-N,N′-Bis(3,5-di-tert -butylsalicylidene)-1,2cyclohexanediamine), as further described below.

A Ru catalyst may be prepared from BTBSC and the LDA solution. Forinstance, the preparation can comprise stirring a mixture of BTBSC (0.02equiv; e.g., 0.04 M) in THF (tetrahydrofuran) at 25±5° C. for 30-40 min,and then cooling the mixture to 5±5° C. The LDA solution from above maythen be added slowly to this mixture at 5±5° C. and the mixture stirredfor approximately 60 min. To the resulting mixture is added, inportions, [Ru(pcymene)Cl₂]₂ (0.02 equiv, assuming 2 equiv Ru/mole of[Ru(p-cymene) Cl₂]₂). The reactor is purged three times with N₂. Themixture is stirred at 25±5° C. for 30-40 min. Lastly, VBF (Stage 6)solution (ca. 0.01 equiv) in TBME is added to this mixture. Theresulting mixture is stirred at 20-25° C. for at least approximately 8hours. The resulting Ru catalyst mixture is used directly in thesubsequent cyclopropanation of VBF step.

VBF (Stage 6) may undergo cyclopropanation. For instance, in oneembodiment, such a preparation may comprise adding toluene (e.g., 20 kg)to the VBF (Stage 6) solution (1.00 equiv) prepared as described for thepreceding step in TBME (e.g., weight of solution (kg)=8.9/assay %) anddistilling the mixture at<100 torr and<50° C. until about 20 L ofresidue remains in the reaction vessel. Toluene (e.g., 60 L) is added,and the mixture is again distilled at<100 torr and<50° C. until about 20L of residue remains in the reaction vessel. The batch residue is cooledto 30±2° C., and the Ru catalyst prepared above is added. The Rucatalyst charge can include an amount of approximately 0.02 molarequivalents. To this mixture is added a solution of EDA in toluene over8-16 hr at 30±2° C. The ethyl diazoacetate charge can includeapproximately 2.5 molar equivalents. The mixture is stirred for at leastapproximately 3 hr at 30±2° C. after the addition is complete. Materialfor which UPLC analysis shows NMT approximately 2.0% VBF (Stage 6) isused directly in the next preparation step, described in further detailbelow.

VEC-int-1 (Stage 7) may undergo a saponification. An illustrativeexample may include adding 45% aqueous NaOH (4 equiv), 55% aqueoustetrabutylammonium hydroxide (TBAH; 0.45 equiv) and tap water (e.g., 10L) to the final reaction mixture from the cyclopropanation of VBF. Thismixture is then stirred at 50-70° C. for 16-18 hr until HPLCindicates<2.0% VEC-int-1 (Stage 7). If the limit is not met, stirring iscontinued at 50-70° C. for 2-4 hr and the analysis is repeated. Once thelimit is met, the mixture is cooled to 25-30° C. Tap water (e.g., 60.0L) is added and the mixture is stirred for at least approximately 30min, and settled for 30-40 min. The organic layer is discarded. TBME(e.g., 107.0 kg) is added to the resulting aqueous layer and the mixtureis cooled to 0-10° C. Phosphoric acid (85% aqueous, e.g., 24.0 kg) isadded slowly at 0-25° C. until the pH of the aqueous layer is 4.0-4.5.If necessary, 10% aqueous NaOH is added to bring the pH into this range.The mixture is then stirred for at least approximately 30 min andsettled for another 30-40 min, the aqueous layer being discarded. Tapwater (e.g., 70.0 L) is added and the mixture is stirred for at leastapproximately 30 min and settled again for approximately 30-40 min, andthe aqueous layer is discarded. This tap water wash may be repeated, forinstance three more washes may be utilized.

Lastly, the Intermediate 3 (Stage 9) (DAA salt) may be formed. In anillustrative example, TBME (e.g., 22.9 kg/kg of VBF (Stage 6)) andethanol (EtOH; anhydrous, e.g., 4.49 kg/kg of VBF (Stage 6) may be addedto the resulting organic layer from the saponification preparation stepabove. The ratio of Intermediate 2 (Stage 8) to TBME may be included ina range of 0.040-0.079 kg Intermediate 2 (Stage 8)/L TBME, and in afurther embodiment may comprise a set point of 0.040 kg Intermediate 2(Stage 8)/L TBME. In one embodiment, the ratio of TBME (kg):EtOH (kg)may be 7.78-9.08, and in a further embodiment may be 7.78. Next,(+)-dehydroabietylamine (1.44 equiv) as a 28% wt/wt solution in TBME maybe added to the resulting mixture. In one embodiment, the(+)-dehydroabietylamine charge may be 1.44-1.76 molar equivalents, andin a further embodiment may be 1.44 molar equivalents. This reactionmixture may be heated to 45-55° C. and stirred for NLT 20 min, cooled to25-30° C. in a period of NLT 2 hr and stirred at this temperature forNLT 1 hr, heated to 45-55° C. and stirred for NLT 20 min, cooled to15-25° C. in a period of NLT 2 hr and stirred for NLT 4 hr, cooled to0-5° C. in a period of NLT 1 hr and stirred for NLT 1 hr, and theprecipitated solid is collected by centrifugation, washed with TBME, andspun, e.g., at full speed for 20±5 min. The collected wet cake is addedto ethanol (anhydrous, e.g., 11.2 kg/kg of VBF (Stage 6)) that has beencooled to 0-5° C. The mixture is stirred at this temperature for 30-40min and then centrifuged, e.g., at full speed for 20±5 min. This washedwet cake is subjected to purity analysis by HPLC. Material meetingpre-set specifications, e.g., (R,R)-trans-Intermediate 3 (Stage 9) NLT99.0 area % and total impurities NMT 2.0%, is dried at NMT 80 torr and60±5° C. for NLT 12 hr until loss on drying (LOD) meets a pre-setspecification e.g., LOD NMT 2.0%. Material failing this specification isdried further at NMT 80 torr and 60±5° C. for NLT 6 hr and re-sampled.

Material meeting the specification is released. If the wet cake failsthe purity test, it is processed again. The second process may compriseadding the wet cake to a cooled (e.g., 0-10° C.) mixture of 45% aqueousNaOH (e.g., 3.60 kg/kg of VBF (Stage 6)), tap water (e.g., 11.9 kg/kg ofVBF (Stage 6)) and toluene (e.g., 4.49 kg/kg of VBF (Stage 6)), stirringfor about 30 min, settling for about 30 min, and phase separation. Tothe aqueous layer is added TBME (e.g., 12.0 kg/kg of VBF (Stage 6)) andthe mixture is cooled (e.g., to 0-10° C.). The pH of the aqueous layeris adjusted with phosphoric acid (85% aqueous, e.g., 24.0 kg) and, ifnecessary, 10% aqueous NaOH to a value of 4.0-4.5. After thorough mixingand settling, the layers are separated, and the organic phase is washedseveral times with tap water. Formation, isolation, drying and LOD andpurity analysis of the Intermediate 3 (Stage 9) DAA salt is repeated asdescribed above. Material meeting the specification is released.

Synthesis of(1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl)Cyclopropanecarboxamide(Intermediate 4) (Stage 10)

The synthesis of Intermediate 4 can comprise liberation of the freecarboxylic acid from (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylic acid (+)-dehydroabietylamine salt (Intermediate3) followed by conversion via the corresponding acid chloride to theamide, (1R,2R)-2-(2,3-dihydrobenzofuran -4-yl) cyclopropane-carboxamide(Intermediate 4 (Stage 10)). Said reaction sequence is illustrated inthe following scheme:

In an illustrative example, Intermediate 4 may be synthesized by addingIntermediate 3 (Stage 9) (1 equiv, e.g., 20.0-21.0 kg) to a firstreaction mixture of tap water (e.g., 5.2 L/kg of Intermediate 3 (Stage9)), 45% aqueous NaOH (4 equiv), and toluene (e.g., 1.8 kg/kg ofIntermediate 3 (Stage 9)) at 20-30° C. The mixture is then stirred at25-30° C. for NLT 30 min and settled for 30-40 min, and the organiclayer discarded. Toluene (e.g., 1.8 kg/kg of Intermediate 3 (Stage 9))is added to the aqueous layer, followed by stirring for NLT 60 min,settling for 30-40 min and discarding the organic layer. The toluenewash can be repeated. Next, sodium chloride (e.g., 0.3 kg/kg ofIntermediate 3 (Stage 9)) is added to the remaining aqueous layer. Thetemperature is adjusted to 15-20° C. Butyl acetate (e.g., 1.2 kg/kg ofIntermediate 3 (Stage 9)) is added. Hydrochloric acid (32% aqueous, 2.9equiv) is added slowly. The temperature is maintained at 15-20° C. whilethe mixture is stirred for NLT 60 min and settled for 30-40 min. If thepH of the aqueous layer is more than 3, additional 32% HCl is addeduntil the pH is less than 3. The layers are separated, and the organiclayer is set aside for later use. The aqueous layer is added to butylacetate (e.g., 1.1 kg/kg of Intermediate 3 (Stage 9)). The temperatureis maintained at 15-20° C. while the mixture is stirred for NLT 60 minand settled for 30-40 min. The aqueous layer is discarded. The organiclayers are combined and distilled at<100 torr and a pot temperature ofNMT 82° C. until the batch residue is about 30 L. The distillate isdiscarded. Butyl acetate (e.g., 0.71 kg/kg of Intermediate 3 (Stage 9))is added to the batch residue. This mixture is distilled at<100 torr anda pot temperature of NMT 82° C. until the batch residue is about 30 L.The distillate is discarded. This step is repeated one or two more timesuntil Karl Fischer moisture analysis indicates a value of less thanapproximately 0.1%. The batch residue is cooled to 15-20° C. DMF (0.03equiv) and thionyl chloride (1.3 equiv) are added. The mixture is heatedto 50-55° C., stirred for 1.5-2.0 hr and cooled to 21±4° C., andanalyzed by HPLC. Material meeting pre-set specifications, e.g.,Intermediate 2 (Stage 8) NMT 1.0%, is further processed. If thisspecification is not met, additional thionyl chloride (0.12 equiv) isadded, and the mixture is heated to 50-55° C., stirred for 1.5-2.0 hr,cooled to 21±4° C., and re-sampled. Following this, a mixture ofammonium hydroxide (9.0 equiv) and tap water (e.g., 0.8 L/kg ofIntermediate 3 (Stage 9)) is cooled to 0-5° C. The acid chloridesolution from the previous step meeting the pre-set specification isadded in portions while maintaining the batch temperature at 0-10° C.After the addition, stirring is continued for 30-40 min at 0-10° C. Thenn-Heptane (e.g., 1.3 kg/kg of Intermediate 3 (Stage 9)) is added, andstirring is continued for 2-3 hr at 0-10° C. The resulting precipitateis collected by centrifugation. The wet cake is washed in the centrifugecart with tap water (e.g., 15 L/cart) and then spun at full speed for20±5 min. This wet cake is added to a mixture of butyl acetate (e.g.,0.71 kg/kg of Intermediate 3 (Stage 9)) and n-heptane (e.g., 0.3 kg/kgof Intermediate 3 (Stage 9)) at 0-10° C. The resulting mixture isstirred for 30-40 min at 0-10° C. and then centrifuged at full speed for20±5 min. The wet cake is analyzed by HPLC to determine if pre-setspecifications are met, e.g., Intermediate 4 (Stage 10) NLT 98.0%. Ifthis specification is not met, the wet cake can be added to anothermixture of butyl acetate and n-heptane, the stirring and centrifugationrepeated until the wet cake meets the specification as analyzed by HPLC,e.g., Intermediate 4 (Stage 10) NLT 98.0%. The wet cake that meets thepre-set specifications is dried at NMT 80 torr and 45±5° C. for NLT 12hr until pre-set specifications are met, e.g., LOD is NMT 1.0% andmoisture by Karl Fischer analysis is NMT 0.2%. Material failing thesepre-set specifications is dried further at NMT 80 torr and 45±5° C. forNLT 6 hr and resampled. Material meeting the pre-set specifications isreleased as Intermediate 4 (Stage 10), which may be stored in one ormore polyethylene (PE) bags, which may also be sealed within a paperdrum.

Synthesis of ((1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl)Cyclopropyl)Methanaminium Chloride (Intermediate 5)

The synthesis of Intermediate 5 can comprise contacting and reacting(1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide(Intermediate 4) with Lithium aluminum hydride in an organic solvent,followed by aqueous workup and isolation of the resulting amine as itshydrochloride salt. Said reaction is illustrated in the followingscheme:

In one example, Intermediate 5 (Stage 11) may be synthesized by theabove scheme, wherein the synthesis may include the following procedure.For example, a reactor (e.g., SS316) is cleaned with refluxing acetone(e.g., 100 kg), drained, dried under vacuum for 1-2 hr, and filled withN₂ gas. The Intermediate 4 (Stage 10) (1.00 equiv) made above and THF(e.g., 8 kg/kg of Intermediate 4 (Stage 10)) are added to the dryreactor and cooled to −10° C. Lithium aluminum hydride (LAH) solution(10% in THF, 3.5-3.8 equiv, where 1 equiv=1 mol/mol of Intermediate 4(Stage 10)) is added in portions while keeping the batch temperature NMT25° C. The LAH feed line is rinsed with THF (e.g., 10 kg). The mixtureis warmed to 20-30° C. and stirred for 20-30 min. The mixture is thenwarmed slowly to 65-70° C. while maintaining an internal pressure of NMT0.1 kg/cm₂. This mixture is stirred at 65-70° C. for 3-4 hr, cooled to15-25° C., and analyzed by HPLC to determine if pre-set specificationsare met, e.g., Intermediate 4 (Stage 10) NMT 1.0%. If this limit is notmet, the previous warming and cooling whilst stirring is repeated. UponHPLC indicating that not more than approximately 1.0% of

Intermediate 4 remains, the reaction mixture is cooled to −5˜5° C.Aqueous THF (91%, e.g., 1.09 kg/kg of 10% LAH) is added at NMT 25° C.,and stirring is continued for 20-30 min. The water charge (as aqueousTHF) may be 1.0-1.1 L of water/kg of LAH, and in a further embodimentmay be 1.1 L of water/kg of LAH. Aqueous NaOH (5.3%, e.g., 0.37 kg/kg of10% LAH) is added at NMT 25° C. (causing an exothermic reaction), andstirring is continued for 20-30 min. The NaOH charge may be 0.17-0.19mol/mol of LAH, and in a further embodiment may be 0.18-0.19 mol/mol ofLAH. The mixture is warmed slowly to 65-70° C., stirred for 3-4 hr, andcooled to 15-25° C. The mixture is filtered, using THF (e.g., 30 kg) tocomplete the transfer of the reaction mixture into the filter. Thefiltrate is kept in the receiver. This filter cake is then transferredback to the reactor and resuspended in fresh THF (1.3 kg/kg of 10% LAH).The mixture is stirred at 15-25° C. for 1-1.5 hr, and then filtered,using THF (0.65 kg/kg of 10% LAH) to complete the transfer again. Thewet cake is discarded. The combined filtrates are distilled at<100 torrand NMT 40° C. until the batch residue is about 40 L. The distillate isdiscarded. TBME (e.g., 30 kg) is added to the remaining batch residueand the mixture is distilled at<100 torr and NMT 40° C. until the batchresidue is about 40 L. The distillate is discarded. TBME (e.g., 20 kg)and tap water (e.g., 20 kg) are then added to the batch residue and themixture is stirred for 60-70 min at 15-20° C. and settled for 30-40 min.The aqueous layer is discarded. Tap water (e.g., 20 kg) is then added tothe organic layer and the mixture is stirred for 60-70 min at 15-20° C.and settled for 30-40 min. The aqueous layer is discarded. The organiclayer is analyzed by inductively coupled plasma—optical emissionspectroscopy to determine if pre-set specifications are met, e.g., LiNMT 10 ppm, Al NMT 10 ppm. If these specifications are not met, the washwith tap water is repeated until the specifications are met. Followingmeeting the specifications, anhydrous ethanol (e.g., 30 kg) is added tothe organic layer meeting the specifications and the mixture isdistilled at<100 torr and a pot temperature of NMT 40° C. until thebatch residue is about 40 L. The distillate is discarded. Anhydrousethanol (e.g., 82.8 kg) is added to the residue and the mixture is againdistilled at<100 torr and a pot temperature of NMT 40° C. until thebatch residue is about 40 L. The distillate is discarded. Thisazeotropic distillation step may be repeated one or two more times untilpre-set specifications are met, e.g., Karl Fischer moisture analysisindicates a value of NMT 0.5%. The batch residue is then cooled to15-25° C. and TBME ((tert-butyl methyl ether) e.g., 13.8 kg/kg ofIntermediate 4 (Stage 10)) is added to the residue. The mixture iscooled to 0-5° C. Hydrogen chloride (HCl) gas (3.3 equiv) is added inportions at NMT 25° C., and stirring is continued for 60-70 min at20-25° C. after the addition is complete. If the pre-set specification,e.g., pH NMT 1.0, is not met, more HCl gas is added until thespecification is met. The resulting precipitate is collected bycentrifugation. The wet cake is washed in the centrifuge cart withTBME:EtOH (anhydrous, 1.5:1.0, e.g., 5.0 kg), and the cake iscentrifuged at full speed for 20±5 min. The cake is analyzed by HPLC todetermine if pre-set specifications are met, e.g., Intermediate 5 (Stage11) NLT 98.0%. If this specification is not met, the cake can bere-suspended in TBME:EtOH (anhydrous, 1.5:1.0, e.g., 6.6 kg/kg ofIntermediate 4 (Stage 10)), and centrifuged and washed as above untilthe specification is met. The cake that meets the specification is driedat NMT 80 torr and 35±5° C. for NLT 12 hr until LOD is NMT 1.0%.Material which does not meet pre-set specifications is dried further atNMT 80 torr and 35±5° C. for NLT 6 hr and re-sampled. Material meetingthe pre-set specifications is released as Intermediate 5 (Stage 11). Theresulting Intermediate 5 (Stage 11) may be stored in one or more PEbags, which may in turn be sealed in a paper drum.

Synthesis ofN-(((1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl)Cyclopropyl)-Methyl)Propionamide (Tasimelteon, Pre-Particle Size Reduction (i.e., Unmilled))

Following the synthesis of the above disclosed intermediates,tasimelteon, which is unmilled, may be synthesized. The end stepsynthesis of tasimelteon can comprise contacting and reacting((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropyl)methanaminiumchloride (Intermediate 5) with propionyl chloride in the presence oforganic solvent and base. Said reaction is illustrated in the followingscheme:

For example, in an illustrative end step synthesis, a first reactionmixture is prepared by adding 45% aqueous NaOH (8 equiv) to a mixture ofIntermediate 5 (Stage 11, 1.00 equiv), TBME (e.g., 15.2 kg/kg ofIntermediate 5 (Stage 11)) and tap water (e.g., 14.6 kg/kg ofIntermediate 5 (Stage 11)) at 0-10° C. Propionyl chloride (1.28-1.46equiv) is added at 5-10 ° C., after which the mixture is stirred at thistemperature for 90-120 min. This mixture can be analyzed by HPLC todetermine if the resultant solution meets pre-set specifications, e.g.,Intermediate 5 (Stage 11) NMT 0.10%. After stirring and then settling,at 25-30 C, the aqueous layer is discarded. The organic layer can bewashed with 5% aqueous NaOH and then twice with water. The organic layeris filtered and distilled at about<100 Torr (1 Torr ˜=1 mmHg=133.3 Pa)and about</=58° C. and the distillate is discarded. Into the potcontaining this residue is charged 95% EtOH (e.g., 24.0 kg) via a cleanfilter. The resulting mixture is distilled at about<100 Torr and about</=58° C., the distillate is discarded, and this solvent exchange stepis repeated two more times with fresh 95% EtOH. To the pot containingthe residue is added 95% EtOH and process water via a filter. The volumeof EtOH may be 2.8-5.0 equivalent volumes, where 1 equivalent volume=1 Lof EtOH/kg of tasimelteon (unmilled), assuming 90% yield of tasimelteon(unmilled) based on Intermediate 5 (Stage 11) input. In anotherembodiment, the volume of EtOH may be 3.0-5.0 equivalent volumes. Theratio of EtOH:water may be 0.7:1-1.4:1 (v/v). In another embodiment, theratio of EtOH:water may be 1.0:1.0. The mixture may be warmed to 35-40°C. and stirred for 30-40 min, cooled to 13-17° C. over a period of60-120 min, and stirred at 13-17° C. for 60-90 min. If crystallizationdoes not occur, the mixture may be seeded with tasimelteon (unmilled)crystals. Following addition of process water (e.g., 19.2 kg/kg ofIntermediate 5 (Stage 11) added over 2-2.5 hr at 10-15° C. followed bystirring at the same temperature for 60-90 min), the precipitate iscollected by centrifugation and the cake is analyzed by HPLC todetermine if the product meets pre-set specifications, e.g., tasimelteonNLT 99%, Impurities 5 and 6 NMT 0.15% a/a, and other individualimpurities NMT 0.10% a/a, e.g., Impurities 1, 2, 3, 4, and 7. Materialmeeting said pre-set specifications is washed, e.g., with n-heptane, andthen dried, e.g., until LOD is NMT 0.7%. The dried material is alsoanalyzed for particle size. Material not meeting the pre-setspecifications, e.g., for Impurities 5 and 6 is transferred back to thereaction vessel and recrystallized as described above, i.e., byre-dissolving in warm EtOH:water, filtering, allowing the mixture tocool and crystallize, further precipitating by slow addition of waterand collecting by centrifugation. Such re-processed material that meetssaid impurity specifications is washed, dried and analyzed as describedabove, after which it is released for milling, discarded, or furtherre-processed.

The above-described end-step synthesis is illustrative only. Forexample, other organic solvents or mixtures thereof can be used in placeof tert-butyl methyl ether (TBME). Bases other than or in addition toNaOH can also be employed. The solvent for crystallization can be anaqueous solvent, such as an aqueous C1-C4 alcohol, e.g., methanol,ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, ortert-butanol, or a mixture of organic solvents such asMTBE-EtOH-cyclohexane.

Tasimelteon drug substance is stored as the unmilled drug substance andmilled on an as-needed basis, immediately prior to its use in capsuledrug product manufacturing. It has been found that use of a jet mill anda dry nitrogen atmosphere is advantageous in achieving uniform particlesize with good handling characteristics and minimal loss.

Drug substance meeting particle size specifications (e.g., D_(0.1)<15 μm(i.e., 10% of the particles are 15 μm in diameter or less); D_(0.5)<30μm; D_(0.9)<75 μm for in process and (i) a D₉₀ specification set at<105μm; (ii) a D₅₀ specification set at<45 μm; and (iii) a D₁₀ specificationset at<15 μm for release) is tightly sealed, e.g., in PE bags and/oraluminum bags, e.g., with a dessicant such as a silica dessicant.

When manufacturing pharmaceutical grade tasimelteon, i.e., tasimelteonthat is intended for human use, good manufacturing practices (GMP) areemployed such as may be required by regulatory bodies in relevantjurisdictions. Bulk pharmaceutical grade tasimelteon is then mixed withexcipients to prepare bulk formulated tasimelteon and then formed intoan appropriate pharmaceutical dosage form, such as capsules, eachcomprising 10 mg to 100 mg, e.g., 20 mg, of tasimelteon.

The description above refers to milling. However, the skilled personwill recognize that other particle size reduction techniques, e.g.,sieving, high shear fluid processing, etc., can also be employed.Similarly, milling techniques other than jet milling, e.g., grinding,cryogenic grinding, cutting or impacting, etc., can also be employed.

While the invention has been described in detail in connection with onlya limited number of embodiments, it should be readily understood thatthe invention is not limited to such disclosed embodiments. Rather, theinvention can be modified to incorporate any number of variations,alterations, substitutions or equivalent arrangements not heretoforedescribed, but which are commensurate with the spirit and scope of theinvention. Additionally, while various embodiments of the invention havebeen described, it is to be understood that aspects of the invention mayinclude only some of the described embodiments. Accordingly, theinvention is not to be seen as limited by the foregoing description, butis only limited by the scope of the appended claims.

What we claim is:
 1. A composition comprising tasimelteon prepared by aprocess comprising the steps of: contacting and reacting(1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carboxamide with areducing agent and an acid in an organic solvent to prepare((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or asalt thereof; and contacting and reacting the((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropyl)methanamine with apropionylating reagent to prepare tasimelteon.
 2. The composition ofclaim 1, wherein the reducing agent comprises LiAlH₄.
 3. The compositionof claim 1, wherein the acid comprises HCl.
 4. The composition of claim1, wherein the organic solvent comprises TBME.
 5. The composition ofclaim 1, wherein the propionylating agent comprises propionyl chloride.6. The composition of claim 1, wherein the propionylation step furtherincludes an organic solvent and a base.
 7. The composition of claim 6,wherein the base comprises NaOH.
 8. The composition of claim 1, whereinthe (1R,2R)-2-(2,3-dihydrobenzofuran -4-yl)cyclopropane carboxamide isreduced to prepare((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a saltthereof.
 9. A pharmaceutical composition comprising the compositionaccording to claim 1 and at least one pharmaceutically acceptableexcipient.